Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype

Kohashi, Kenichi; Oda, Yoshinao; Yamamoto, Hidetaka; Tamiya, Sadafumi; Takahira, Tomonari; Takahashi, Yukiko; Tajiri, Tatsuro; Taguchi, Tomoaki; Suita, Sachiyo; Tsuneyoshi, Masazumi

doi:10.1007/s00432-008-0385-3

Cited by 35 publications

(31 citation statements)

References 20 publications

(34 reference statements)

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“…Consistent with a role in osteosarcoma development, mouse models have shown that loss of Rb can potentiate the development of osteosarcomas in the context of mutant p53 (Berman et al, 2008;Walkley et al, 2008). However, despite the clear role of Rb in osteosarcoma development, attempts to identify a role for Rb in STSs have been met with conflicting reports (Cance et al, 1990;Karpeh et al, 1995;Dei Tos et al, 1996;Kohashi et al, 2008). Attempts to generate STSs in transgenic animals have not demonstrated a causative role for Rb in their development.…”

Section: Lessons From the Earliest Models Of Stsmentioning

confidence: 99%

Animal models of soft-tissue sarcoma

Dodd

Mito

Kirsch

2010

Disease Models &Amp; Mechanisms

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Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies.

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Section: Lessons From the Earliest Models Of Stsmentioning

confidence: 99%

Animal models of soft-tissue sarcoma

Dodd

Mito

Kirsch

2010

Disease Models &Amp; Mechanisms

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“…Alterations in CDKN2A and its downstream effectors Retinoblastoma 1 (Rb1) and Tp53 have been noted in human STS (3,16,17), and one study reported reduced or absent expression of p16 INK4A and/or p14 ARF in human RMS (18). Together, these data implicate both oncogenic Kras and dysregulated p16p19 as clinically relevant, sarcoma-associated lesions.…”

mentioning

confidence: 94%

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Hettmer

Liu

Miller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Soft-tissue sarcomas are heterogeneous cancers that can present with tissue-specific differentiation markers. To examine the cellular basis for this histopathological variation and to identify sarcoma-relevant molecular pathways, we generated a chimeric mouse model in which sarcoma-associated genetic lesions can be introduced into discrete, muscle-resident myogenic and mesenchymal cell lineages. Expression of Kirsten rat sarcoma viral oncogene [ Kras ( G12V )] and disruption of cyclin-dependent kinase inhibitor 2A ( CDKN2A ; p16p19 ) in prospectively isolated satellite cells gave rise to pleomorphic rhabdomyosarcomas (MyoD-, Myogenin- and Desmin-positive), whereas introduction of the same oncogenetic hits in nonmyogenic progenitors induced pleomorphic sarcomas lacking myogenic features. Transcriptional profiling demonstrated that myogenic and nonmyogenic Kras; p16p19 null sarcomas recapitulate gene-expression signatures of human rhabdomyosarcomas and identified a cluster of genes that is concordantly up-regulated in both mouse and human sarcomas. This cluster includes genes associated with Ras and mechanistic target of rapamycin (mTOR) signaling, a finding consistent with activation of the Ras and mTOR pathways both in Kras; p16p19 null sarcomas and in 26–50% of human rhabdomyosarcomas surveyed. Moreover, chemical inhibition of Ras or mTOR signaling arrested the growth of mouse Kras; p16p19 null sarcomas and of human rhabdomyosarcoma cells in vitro and in vivo. Taken together, these data demonstrate the critical importance of lineage commitment within the tumor cell-of-origin in determining sarcoma histotype and introduce an experimental platform for rapid dissection of sarcoma-relevant cellular and molecular events.

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“…16 The genomic landscape causative of ERMS is characterized by a number of genetic lesions and/or somatic mutations that deliberately sustain the activity of different receptors, such as IGF1R, FGFR4 and Patched, [17][18][19][20][21] and related downstream pathways (i.e., RAS/ERK, PI3K/AKT and Sonic Hedgehog signaling). 11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported. [25][26][27][28][29][30] Conversely, ARMS is dominated by the presence of specific chromosomal translocations leading to expression of the fused Pax3-Foxo1 and Pax7-Foxo1 factors, that driving in a cell cycle manner the transcription of several genes normally restricted to the embryonal development favor tumor initiation in some muscle precursors.…”

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confidence: 99%

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

Faggi

Chiarelli

Colombi

et al. 2015

Laboratory Investigation

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Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage-independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. Rhabdomyosarcoma (RMS) is a childhood soft tissue sarcoma exhibiting broad expression of skeletal muscle markers, 1-3 such as Pax7, MyoD, Myogenin, desmin and muscle-specific actin. 4,5 Cells of origin in RMS may be different muscular and non-muscular cell precursors, 6-8 such as muscle satellite cells (SCs), 9-11 and myoblasts 9,10,12-14 or adipocytes, 15 which are responsible of two major histological subtypes known as embryonal (ERMS) and alveolar (ARMS). The most common ERMS variant arises in children usually o5 years on distinct body sites, such as head, neck and genitourinary regions, while ARMS typically arises in the muscular limb extremities of adolescents and is characterized by poorer prognosis. 16 The genomic landscape causative of ERMS is characterized by a number of genetic lesions and/or somatic mutations that deliberately sustain the activity of different receptors, such as IGF1R, FGFR4 and Patched, 17-21 and related downstream pathways (i.e., RAS/ERK, PI3K/AKT and Sonic Hedgehog signaling). 11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported. [25][26][27][28][29][30] Conversely, ARMS is dominated by the presence of specific chromosomal translocations leading to expression of the fused Pax3-Foxo1 and Pax7-Foxo1 factors, that driving in a cell cycle manner the transcription of several genes normally restricted to the embryonal development f...

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Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype

Cited by 35 publications

References 20 publications

Animal models of soft-tissue sarcoma

Animal models of soft-tissue sarcoma

Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

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